Articles in 2015

Po-Ru Loh, Alkes Price and colleagues developed a fast algorithm for multicomponent, multi-trait variance-components analysis and use it to analyze the genetic architectures of schizophrenia and nine complex diseases from the PGC and GERA cohorts. Their analyses support a largely polygenic architecture for schizophrenia and significant genetic correlations for several pairs of GERA diseases.

Ray Ming, Robert Paull, Qingyi Yu and colleagues report the genome sequences of two cultivated pineapple varieties and one wild pineapple relative. Their analysis supports the use of the pineapple as a reference genome for monocot comparative genomics and provides insight into the evolution of crassulacean acid metabolism photosynthesis.

Davide Sosso and colleagues show that SWEET4 hexose transporters are essential for grain filling in both maize and rice, and were likely selected during domestication to enhance sugar import into the endosperm.

Whole-exome sequencing has revolutionized the identification of genes with dominant disease-associated variants for rare clinically and genetically heterogeneous disorders, but the identification of genes with recessive disease-associated variants has been less successful. A new study now provides a framework integrating Mendelian variant filtering with statistical assessments of patients' genotypes and phenotypes, thereby catalyzing the discovery of novel mutations associated with recessive disease.

Three new studies have identified new genes and sequence variants implicated in blood lipids, inflammatory markers, hemoglobin levels and adult height variation in Sardinia. These reports highlight the usefulness of large-scale genotype imputation based on whole-genome sequencing, particularly in isolated populations, in studying the genetics of complex human phenotypes.

Adult T cell leukemia/lymphoma (ATL) is a neoplasm linked to human T-lymphotropic virus type-1 (HTLV-1) infection and is refractory to current combination chemotherapy. A large genomic and transcriptomic study of ATL now provides detailed insight into the molecular lesions implicated in the development of this T cell malignancy.

A large collection of human genomes from Sardinia is reported in three linked papers that implicate new genetic variants in the regulation of height, blood lipids, inflammatory markers and hemoglobin levels. These analyses provide new insight into disease susceptibility and evolution in isolated human populations and illuminate the genetics of complex phenotypes.

Yardena Samuels and colleagues report the analysis of 501 melanoma exomes and the identification of RASA2 as a tumor-suppressor gene mutated in 5% of melanomas. RASA2 mutations led to increased RAS activation, and RASA2 loss was associated with shorter patient survival times.

Matthew Maurano, John Stamatoyannopoulos and colleagues identify 64,597 allelically imbalanced SNPs that influence transcription factor occupancy in vivo. Using these data, they develop a general scoring method to identify regulatory variants likely to affect transcription factor occupancy in the human genome.

Timothy Vyse and colleagues report the results of a large-scale association study of systemic lupus erythematosus (SLE). They identify ten new susceptibility loci and implicate aberrant regulation of innate and adaptive immunity genes in disease pathogenesis.

Felix Stickel and colleagues report the results of a genome-wide association study of alcohol-related cirrhosis. They confirm PNPLA3 as a susceptibility locus and identify new association signals in MBOAT7 and TM6SF2.

Lewis Cantley and colleagues report an integrated metabolic and transcriptomic study of non–small cell lung cancer (NSCLC) cell lines. They show that the activity of the serine/glycine biosynthetic pathway in NSCLC is highly heterogeneous and is regulated by NRF2 and that elevated expression of genes in this pathway confers poor prognosis in human NSCLC.

Suneet Agarwal and colleagues use somatic cells and induced pluripotent stem cells from patients with PARN mutations to show that PARN is required for the 3′-end maturation of the telomerase RNA component TERC. Their findings provide a mechanism linking PARN mutations to telomere diseases.

Lavinia Paternoster and colleagues report the results of a large, multi-ancestry genome-wide association study of atopic dermatitis. They identify ten new susceptibility loci harboring candidate genes involved in innate host defense and T cell function.

Matthew Freedman and colleagues show that androgen receptor (AR) binding sites undergo extensive reprogramming during prostate epithelial transformation. They further show that FOXA1 and HOXB13 colocalize at reprogrammed AR binding sites in human tumor tissue and are able to reprogram the AR cistrome of an immortalized prostate cell line to resemble that of prostate tumors.

Elliot Stieglitz, Mignon Loh and colleagues report the whole-exome sequencing of diagnostic and relapsed samples from patients with juvenile myelomonocytic leukemia. They identify new recurrent mutations for this disease and find that the number of somatic alterations present at diagnosis may be predictive of clinical outcome.

Hélène Cavé and colleagues genetically profile a cohort of 118 juvenile myelomonocytic leukemia (JMML) samples and uncover mutations in multiple components of the RAS signaling pathway and the PRC2 network. Their study demonstrates an association between JMML clinical outcome and mutational profile and suggests a dose-dependent effect for RAS pathway activation.

Bernhard Radlwimmer and colleagues report whole-genome bisulfite sequencing of 13 Burkitt lymphomas and nine follicular lymphomas. They find that both types of germinal center B cell lymphomas show global hypomethylation compared to normal germinal center B cell precursors and identify regions of differential methylation that correlate with somatic mutations and differential gene expression.

Seishi Ogawa and colleagues report the results of a large-scale sequencing study of adult T cell leukemia/lymphoma. They find recurrent alterations enriched for T cell receptor/NF-κB signaling, T cell trafficking and other T cell pathways and highlight targets for the development of new therapeutics for this intractable cancer.

Matthew Hurles, David FitzPatrick and colleagues report the discovery of four novel Mendelian disorders based on their analysis of exome sequence data from 4,125 families with diverse rare developmental disorders. They present their analytical pipeline as a general strategy for the discovery of genetic causes of autosomal recessive disorders.